Project Summary Zika virus (ZIKV) is primarily transmitted to people through the bite of an infected mosquito from the Aedes genus, mainly Aedes aegypti, although the virus can also be transmitted through sexual intercourse. There is scientific consensus that ZIKV is a causative agent of microcephaly, a birth defect in children born to infected mothers and neuroimmune Guillain-Barr syndrome in infected adults. Even more troubling, vertical transmission of ZIKV is not limited to microcephaly alone, but it is now directly linked to multiple, albeit still severe, dysfunctions in the development of the brain and the eyes, called the Congenital Zika Syndrome. Because ZIKV continues to spread through the Americas, a better understanding of ZIKV pathology along with an efficient means to treat the infection is urgently needed. Accordingly, the focus of our MPI research proposal is to greatly increase our understanding of the changes to brain pathology caused by long-term ZIKV infections, and a practical means to control the virus in a pharmacologically-beneficial manner by repurposing the current FDA-approved anti-viral and anti-malarial pharmaceuticals as cocktails. Importantly, a physiologically-relevant SJL mouse model of ZIKV vertical transmission and chronic infection is employed in our in-depth studies, rather than interferon-knockout animals that perish in a few days post-infection. This project is firmly grounded on volumes of our preliminary data. Our Specific Aims are: (1) Determine the dynamics of fetal brain infection and investigate perinatal consequences following ZIKV vertical transmission in SJL mice, (2) Determine structural and functional consequences to the adult brain following congenital ZIKV infection in SJL mice, and (3) Determine the best treatment regimens for ZIKV infection using inhibitors of different stages of the viral life cycle and their combinations to prevent vertical transmission of ZIKV. Our exceptional and well-balanced multidisciplinary team includes experienced professionals with complementary expertise in the diverse areas of virology, biochemistry, neuro- and stem cell biology, drug design, in silico modeling and statistics, brain development and magnetic resonance microscopy. To accomplish our interrelated Specific Aims in their entirety and in a timely fashion, we will use a plethora of the advanced cellular, molecular and imaging techniques and methodologies which, especially if combined, are not readily available for many others. An additional advantage of our multi-talented team is our extensive, decade-long, studies in flaviviruses. Because our ZIKV-centered research has been already on-going for over a 2-year period, we have already acquired significant momentum in our studies that bodes well for the success of this proposed research project.